POLG NM_002693.2 exon 3 p.Gly268Ala (c.803G>C): This variant has been reported in several individuals with clinical suspicion of POLG related conditions, including progressive external ophthalmoplegias (PEO) (Di Fonzo 2003 PMID:14635118, Del Bo 2003 PMID:14557557, Gonzalez-Vioque 2006 PMID:16401742, Tang 2011 PMID:21880868). Individuals reported in the literature present with this variant in the heterozygous and homozygous state, but the clinical impact of zygosity is unclear. This variant is present in 0.4% (534/126574) of European individuals, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752784). This variant is present in ClinVar (Variation ID:196354). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies suggest a deleterious effect of this variant. However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Furthermore, at least one publication has questioned the pathogenicity of this variant (Tang 2011 PMID:21880868). This, combined with the high minor allele frequency identified in controls, conflicts with the expected pathogenicity of this variant. Therefore, the clinical significance of this variant is uncertain.

A variant of uncertain significance has been identified in the POLG gene. The G268A variant was initially reported in two patients with autosomal recessive progressive external ophthalmoplegia (arPEO) who had multiple DNA deletions in muscle, and both patients had two identifiable POLG variants by sequencing (Di Fonzo et al., 2003). G268A has subsequently been identified in severalpatients with sporadic PEO, hepatocerebral syndrome, or other neurological symptoms suggestive of a mitochondrial disorder who did not have a second identified POLG pathogenic variant on the otherallele (Gonzalez-Vioque et al., 2006; Blok et al., 2009). Blok et al. (2009) concluded that it is unclear whether patients found to harbor a single G268A variant were incidentally found to be carriers of an autosomal recessive POLG pathogenic variant or whether they may have a second unidentifiedpathogenic variant in POLG or another gene that was not detected by the testing methods. Tang et al. (2011) questioned the reported pathogenicity of G268A and reported that in their cohort G268A was present at high frequency; however, it was not found with another POLG pathogenic variant in any oftheir patients. The G268A variant is observed in 78/11562 (0.67%) alleles from individuals of Latino background, including multiple unrelated homozygous individuals in large population cohorts (Lek et al., 2016). The G268A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this variant alters a highly conserved position in the exonuclease domain of the protein where many missense pathogenicvariants have been reported in association with POLG-related disorders (Human DNA Polymerase Gamma Mutation Database). Additionally, in silico analysis predicts the G268A variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, itis unclear whether this variant is a pathogenic variant or a rare benign variant.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

The NM_002693.2:c.803G>C (NP_002684.1:p.Gly268Ala) [GRCH38: NC_000015.10:g.89330133C>G] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16940310 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign.

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